Department of Defense Peer Reviewed Medical Research Program Funding Received

The vision of the PRMRP is to improve the health and well-being of all military service members, veterans, and beneficiaries.

Research projects of affiliated faculty members of the
McGowan Institute for Regenerative Medicine
were recently awarded funds from the Department of Defense Peer Reviewed Medical Research Program (PRMRP). The funding is provided to support select medical research projects of clear scientific merit and direct relevance to military health. The vision of the PRMRP is to improve the health and well-being of all military service members, veterans, and beneficiaries. This program is administered by the U.S. Army Medical Research and Materiel Command through the Office of the Congressionally Directed Medical Research Programs.

Abstract: During the past decade, more than 100 hand and facial transplants have been performed around the world, including over 90 with encouraging outcomes. The University of Pittsburgh is one of the key centers for these exciting new surgical procedures. Key to their success is the timely regrowth of nerves into the new transplanted tissue before muscle has time to degenerate, and the survival of vital arteries that tend to thicken with chronic rejection of the transplant, putting transplanted tissue at risk. Monitoring nerves and arteries is thus essential for appropriate measures to be taken in time and, in the research setting, it is required so that new therapies can be developed. To be safe, monitoring of nerves and arteries in these patients must not involve taking biopsies. Imaging techniques using ultrasound are promising because of their safety and low cost, and recent advances in ultrasound resolution have made subtle changes in nerves and arteries more easily visualized. However, ultrasound still suffers from an inability to accurately record where in a patient a given ultrasound scan has been acquired. The knowledge of scan location is particularly important for comparing ultrasound scans from one month to the next, and from one patient to another.

A technology called ProbeSight is in development to determine and record the location of the ultrasound probe in terms of the particular anatomical structures being scanned. Just as the operator holding the ultrasound probe knows where the scan is being taken by looking at it, so it is possible with a special camera to determine that location automatically. The camera will be mounted directly on the ultrasound probe so that it looks toward the patient. ProbeSight will compare what its camera sees with its own internal “memory” of the patient’s overall appearance. The ProbeSight system can provide a valuable record of location information along with the ultrasound data, so that changes to nerves and arteries at a given place in the patient can be monitored from one day, week, or month to the next.

The proposal has three major aims: (1) to develop the ProbeSight technology from an engineering standpoint, (2) to validate the accuracy and reliability of the technology to determine probe location on artificial phantoms, normal human arms, and the abnormal arms of patients after hand-surgery, and (3) to validate the use of video localized ultrasound images to monitor changes in nerves and arteries over time, after a nerve injury or a hand transplant has occurred.

The technology is inherently safe, economical, non-invasive, reliable, and reproducible. It will facilitate understanding the condition of nerves and arteries after injury and during healing, helping to determine a more timely and accurate treatment strategy. It will provide clinicians and researchers serving patients with hand-transplants and nerve injuries an important new ability to follow nerve regeneration and chronic rejection, enabling effective comparisons across patients and across time. Furthermore, it will offer early diagnosis and preventative management of many other conditions highly relevant to the screening, diagnostic, and therapeutic strategies directed at rehabilitating and restoring functionality in our war-wounded.

Abstract: Trauma to the upper extremity can result in amputation of the injured limb, and severe trauma to the face can result in highly disfiguring injury with severe functional compromise to the vital functions of the head and neck. In these circumstances, the best reconstructive option available is transplantation of the limb or face as a graft to the injured patient from a donor. However, this is associated with significant risks, both surgical and medical. The principal medical risk is the need for long-term suppression of the immune system, with its attendant risk of infection. Researchers have approached this problem by trying to minimize the medications needed for immunosuppression, and by trying to induce tolerance of transplanted tissues in the patient’s immune system.

A novel intervention is proposed to minimize the immune mismatch represented by a face or limb transplant graft: editing of the graft’s DNA to prevent it from displaying the molecules that cause transplant rejection. The plan is to use a novel system called CRISPR/Cas, discovered in microorganisms, to target the major cellular immune markers (called major histocompatibility complex antigens) present on a transplant graft. By specifically silencing these antigens researchers hope to engineer a graft that will not provoke the immune system on transplantation. In this effort, CRISPR/Cas will be used to achieve this silencing in cells in culture as a first step, and then test those cells to verify that they have become less provocative to an immune system on transplantation.